This invention relates to the use of certain alpha 2 delta ligands for the treatment of fibromyalgia and other central nervous system disorders. Fibromyalgia (FM) is a chronic syndrome characterized mainly by widespread pain, unrefreshing sleep, disturbed mood, and fatigue. The main symptoms fibromyalgia include pain, sleep, mood disturbances and fatigue. Syndromes commonly associated with fibromyalgia include irritable bowel syndrome, and migraine headaches, among others. Success of treating fibromyalgia with a single pharmacological agent has been characterized as modest and results of clinical trials have been characterized as disappointing. It is believed that based on current understanding of the mechanisms and pathways involved in fibromyalgia, multiple agents will be required, aimed at the major symptoms of pain, disturbed sleep, mood disturbances, and fatigue. Fibromyalgia patients are often sensitive to side effects of medications, a characteristic perhaps related to the pathophysiology of this disorder (Barkhuizen A., Rational and Targeted Pharmacologic Treatment of Fibromyalgia, Rheum. Dis. Clin. N. Am., 2002; 28: 261-290; Leventhal L. J., Management of Fibromyalgia, Ann. Intern. Med., 1999;131:850-8).
While fibromyalgia is a complex disorder with multiple facets, this complexity can be well assessed (Yunus M. B., A Comprehensive Medical Evaluation of Patients with Fibromyalgia Syndrome, Rheum. Dis. N. Am., 2002; 28:201-217). The diagnosis of FM is usually based on the 1990 recommendations of the American College of Rheumatology classification criteria (Bennett R. M., The Rational Management of Fibromyalgia Patients, Rheum. Dis. Clin. N. Am., 2002; 28: 181-199; Wolfe F., et al., The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia: Report of the Multicenter Criteria Committee, Arthritis Rheum., 1990; 33:160-72). Evaluation, management, and pharmacological treatment of fibromyalgia have been reviewed (Barkhuizen A., Rational and Targeted Pharmacologic Treatment of Fibromyalgia, Rheum. Dis. Clin. N. Am., 2002; Buskila D., Fibromyalgia, Chronic Fatigue Syndrome and Myofacial Pain Syndrome, Current Opinions in Rheumatology, 2001; 13: 117-127; Leventhal L. J., Management of Fibromyalgia, Ann. Intern. Med., 1999; 131:850-8; Bennett R. M., The Rational Management of Fibromyalgia Patients, Rheum. Dis. Clin. N. Am., 2002; 28: 181-199; Yunus M. B., A Comprehensive Medical Evaluation of Patients with Fibromyalgia Syndrome, Rheum. Dis. N. Am., 2002; 28:201-217).
Restless Legs Syndrome (RLS) has been characterized by the minimal diagnostic criteria: (a) desire to move the extremities, often associated with paresthesias/dysesthesias; (b) motor restlessness; (c) worsening of symptoms at rest with at least temporary relief by activity, and (d) worsening of symptoms in the evening or night. Other features commonly seen in RLS include sleep disturbance, periodic limb movements in sleep and similar involuntary movements while awake, a normal neurological examination in the idiopathic form, a tendency for the symptoms to be worse in middle to older age, and, in some cases, a family history suggestive of an autosomal dominant mode of inheritance. See Walters A. S.; Toward a Better Definition of the Restless Legs Syndrome; The International Restless Legs Syndrome Study Group; Mov. Disord. (1995) 10(5): 634-42. See also, Bhatia M. and Bhowmik D.; Restless Legs Syndrome in Maintenance Haemodialysis Patients; Nephrol. Dial. Transplant., (2003) 18: 217. Restless legs syndrome can be a primary disorder, or a secondary disorder associated with, for example, renal insufficiency, heredity, pregnancy, poliomyelitis, infectious diseases, avitaminosis, different types of anemia, diabetes, and certain drugs (e.g. prochloroperazine, lithium, and mianserin).
Gabapentin, pregabalin and other alpha 2 delta ligands including 4H-[1,2,4]oxadiazol-5-one, C-[1-(1H-Tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (1α,3α,5α)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, and (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid, and pharmaceutically acceptable salts and solvates thereof, are referred to in U.S. Pat. No. 4,024,175; U.S. Pat. No. 4,087,544; U.S. Pat. No. 6,306,910; WO 99/21824, WO 01/90052, WO 01/28978, EP 0 641 330, WO 98/17627, and WO 00/76958. The foregoing patents and applications are incorporated herein by reference in their entirety.
The compounds employed in the methods of the present invention are mono- and disubstituted 3-propyl gamma-aminobutyric acids. U.S. patent application Ser. No. 10/009,938 filed Dec. 10, 2001, and Ser. No. 10/324,929 filed Dec. 20, 2002, refer to the compounds employed in the methods of the present invention discussed below and disclose various utilities for these. The entire contents of application Ser. Nos. 10/009,938 and 10/324,929 are hereby incorporated herein by reference.